Mechanisms of long-term maintenance of lung tissue-resident memory CD8 T cells

项目概要/摘要： 尽管有季节性疫苗，但流感病毒仍然是人类健康的重要负担， 每年感染全世界数百万人当前流感疫苗策略的有限功效主要是 这是由于抗原性转变，这使得病毒能够逃避已建立的抗体反应。因此，开发新的 能够识别不同流感病毒株的广泛保护性反应的策略， 重要性一个潜在的策略是开发一种基于T细胞的疫苗，可以识别保守的内部 表位，并在许多流感病毒株中提供保护性免疫。虽然细胞免疫不能 预防流感感染，预先存在的抗病毒T细胞可以限制病毒复制和疾病的严重程度。肺 组织驻留记忆性CD8 T细胞（CD8 TRM）是建立的记忆性T细胞的关键子集 在原发性呼吸道感染后，它们仍然位于肺组织内，在那里它们提供快速的 对随后呼吸挑战的保护。然而，尽管在其他屏障中鉴定出CD8 TRM， 组织如皮肤和肠道已被证明保持稳定，并提供持久的保护，CD8 肺中的TRM随时间逐渐下降。重要的是，我们的初步研究表明，肺CD8 TRM与呼吸道感染（包括流感）的细胞免疫力下降相关。目前我们的 对肺中组织驻留记忆CD8 T细胞维持机制的了解 仍然有限。我们的小组还确定了几种策略，包括用重组的 腺病毒载体和重组流感病毒的初免-加强方法，这导致了长时间的 小鼠肺中流感特异性CD8 TRM的长期维持。我们的主要目标是确定 在这些研究之后观察到的负责增强CD8肺TRM寿命的机制 感染/免疫战略。这项研究的结果将为未来设计细胞介导的流感病毒提供信息。 通过对肺TRM的维持提供有价值的见解，从而对细胞免疫的持久性进行研究， 对呼吸道病原体免疫。

Project Summary/Abstract: Despite the availability of a seasonal vaccine, influenza virus remains a critical burden to human health, infecting millions worldwide every year. The limited efficacy of current influenza vaccine strategies is largely due to antigenic shift, which allows the virus to evade established antibody responses. Thus, developing new strategies to elicit broadly protective responses that can recognize diverse influenza strains is of great importance. One potential strategy is to develop a T-cell based vaccine that could recognize conserved internal epitopes and provide protective immunity across many influenza strains. While cellular immunity cannot prevent influenza infection, pre-existing antiviral T cells can limit viral replication and disease severity. Lung tissue-resident memory CD8 T cells (CD8 TRM) are a critical subset of memory T cells that are established following primary respiratory infection and remain localized within the lung tissue, where they provide rapid protection against subsequent respiratory challenge. However, whereas CD8 TRM identified in other barrier tissues such as the skin and gut have been shown to remain stable and provide long-lasting protection, CD8 TRM in the lung gradually decline over time. Importantly, our preliminary studies show that the loss of lung CD8 TRM correlates with a decline in cellular immunity to respiratory infection, including influenza. Currently, our knowledge of the mechanisms governing the maintenance of tissue-resident memory CD8 T cells in the lung remains limited. Our group has also identified several strategies, including immunization with a recombinant adenovirus vector and a prime-boost approach with recombinant influenza viruses, which result in the long- term maintenance of influenza-specific CD8 TRM in the lungs of mice. Our major objective is to identify the mechanisms responsible for the enhanced longevity of CD8 lung TRM observed following these infection/immunization strategies. The results of this study will inform future design of cell-mediated influenza vaccines by providing valuable insight into the maintenance of lung TRM, and thus, the durability of cellular immunity to respiratory pathogens.